In recent years fundamental advances have been made in the development of chemical agents and regimens of therapy to combat neoplastic diseases. Despite these continuing advances, cancers continue to exact intolerable levels of human pain and suffering. The need for new and better methods of treating neoplasms and leukemias continues to fuel efforts to create new classes of compounds, especially in the area of inoperable or metastatic solid tumors, such as the various forms of lung cancer. Of the one million new cases of cancer diagnosed in the United States each year, more than 90% represent non-hematopoetic tumors, where improvements in five-year survival rates have been modest, at best.
The recent avalanche of information regarding the basic biological processes involved in neoplasms has led to a deeper understanding of the heterogeneity of tumors. Ongoing work has led to the realization that individual tumors may contain many subpopulations of neoplastic cells that differ in crucial characteristics such as karyotype, morphology, immunogenicity, growth rate, capacity to metastasize, and response to antineoplastic agents.
It is because of this extreme heterogeneity among populations of neoplastic cells that new chemotherapeutic agents should have a wide spectrum of activity and a large therapeutic index. In addition, such agents must be chemically stable and compatible with other agents. It is also important that any chemotherapeutic regimen be as convenient and painless as possible to the patient.
This invention reports a series of sulfonylureas which are useful in the treatment of solid tumors. These compounds are orally active--which, of course, results in less trauma to the patient--and are relatively non-toxic. These compounds also have an excellent therapeutic index. The compounds and their formulations are novel.
Many sulfonylureas are known in the art. Certain of these compounds are known to have hypoglycemic activities, and have been used medicinally as such agents. In addition, sulfonylureas have been taught to have herbicidal and antimycotic activities. General reviews of compounds of this structural type are taught by Kurzer, Chemical Reviews, 50:1 (1952) and C. R. Kahn and Y. Shechter, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, (Gilman, et al., 8th ed. 1990) 1484-1487. Some diarylsulfonylureas have been reported as being active antitumor agents. e.g., U.S. Pat. No. 4,845,128 of Harper, et al. (1989); European Patent Publication 0222475 (published May 20, 1987); European Patent Publication 0291269 (published Nov. 17, 1988); Grindey, et al., American Association of Cancer Research, 27:277 (1986); and Houghton et al., Cancer Chemotherapy and Pharmacology, 25:84-88 (1989). There is no suggestion in these references of the indenesulfonylureas of the instant application or that these compounds would be useful as antitumor agents.
Ongoing trials with the broad spectrum antineoplastic agent sulofenur [N-(indan-5-sulfonyl)-N'-(4-chlorophenyl)urea] have shown varying metabolic processes resulting in several major species and many minor species of metabolites. Initial preclinical pharmokinetic and disposition studies have been performed in mice, rats, dogs, and monkeys. These studies showed good adsorption and extensive metabolism of sulofenur in all species. The metabolic breakdown products of interest are as follows:
N-(1-hydroxyindan-5-sulfonyl)-N'-(4-chlorophenyl)urea;
N-(1-ketoindan-5-sulfonyl)-N'-(4-chlorophenyl)urea;
N-(3-hydroxyindan-5-sulfonyl)-N'(4-chlorophenyl)urea;
N-(3-ketoindan-5-sulfonyl)-N'-(4-chlorophenyl)urea;
N-(1,2-dihydroxyindan-5-sulfonyl)-N'-(4-chlorophenyl)urea;
Dihydroxyindanyl metabolite;
p-Chloroaniline;
2-Amino-5-chlorophenyl sulfate;
p-Chloro-oxanilic acid;
W. J. Ehlhardt, Drug Metabolism and Disposition, 19:370-375 (1991).
The main urinary metabolites of sulofenur in animal trials were identified as the mono-hydroxy- and mono-ketoindanyl metabolites. The 1-hydroxy- and 1-ketoindansulfonylureas were also found to be the major metabolites in patients receiving the drug in phase I clinical studies. P. H. Dhahir, et al., Proceedings of the 36th ASMS Conference on Mass Spectroscopy and Allied Topics, pp. 972-973 (1988); W. J. Ehlhardt, supra at 372.
Two of the metabolites, N-(1-hydroxyindan-5-sulfonyl)-N'-(4-chlorophenyl)urea and N-(1-ketoindan-5-sulfonyl)-N'-(4-chlorophenyl)urea, were found to be retained longer in humans than in the other species tested. As a means of minimizing the metabolic formation of these therapeutically inactive metabolites, which contribute to the adverse effects, the instant invention involves the synthesis and method of use of a series of indenesulfonylureas and formulations comprising the same. The formation of the double bond on the five-membered ring is designed to retard or inhibit the formation of the 1-ketoindanyl and 1-hydroxyindanyl metabolites.